Diagnosis and management of allergy and respiratory disorders in sport: An EAACI task force position paper.

Allergy and respiratory disorders are common in young athletic individuals. In the context of elite sport, it is essential to secure an accurate diagnosis in order to optimize health and performance. It is also important, however, to consider the potential impact or consequences of these disorders, in recreationally active individuals engaging in structured exercise and/or physical activity to maintain health and well-being across the lifespan. This EAACI Task Force was therefore established, to develop an up-to-date, research-informed position paper, detailing the optimal approach to the diagnosis and management of common exercise-related allergic and respiratory conditions. The recommendations are informed by a multidisciplinary panel of experts including allergists, pulmonologists, physiologists and sports physicians. The report is structured as a concise, practically focussed document, incorporating diagnostic and treatment algorithms, to provide a source of reference to aid clinical decision-making. Throughout, we signpost relevant learning resources to consolidate knowledge and understanding and conclude by highlighting future research priorities and unmet needs.

Eligibility for anti-fibrotic treatment in idiopathic pulmonary fibrosis depends on the predictive equation used for pulmonary function testing.

BACKGROUND AND OBJECTIVE: Publicly funded therapy for idiopathic pulmonary fibrosis (IPF) relies on percentage predicted values from pulmonary function testing, for example Australian patients must have a forced vital capacity ≥50% (%FVC), transfer factor of the lung for carbon monoxide ≥ 30% (%TLco) and forced expiratory volume in 1 s (FEV1 )/FVC ratio > 0.7. Despite defined cut-off values, no jurisdiction prescribes a reference equation for use; multiple equations exist. We hypothesized that access to subsidized treatment varies depending on the chosen equation. The %FVC and %TLco from different commonly used reference equations across general respiratory patients, and IPF-specific patients, were compared. METHODS: FVC and TLco measurements from a large general respiratory laboratory and the Australian Idiopathic Pulmonary Fibrosis Registry (AIPFR) database were analysed using multiple equations. Differences between %FVC and %TLco for each equation were calculated, with particular interest in classification of patients (%) at the threshold for subsidized treatment. RESULTS: A total of 20 378 general respiratory database results were analysed. The %FVC ≥ 50% increased from 86% with the Roca equation to 96% with Quanjer (European Coal and Steal Community, ECSC) and %TLco≥30% increased from 91% with Paoletti to 98% with Thompson. However, overall increase in eligibility for subsidized treatment was modest, varying from 48.2% to 49.2%. A total of 545 AIPFR database results were analysed. The %FVC ≥ 50% increased from 73% with Roca to 94% with Quanjer (ECSC) and %TLco≥30% increased from 87% with Paoletti to 96% with Miller. Overall eligibility for subsidized treatment in the AIPFR group varied from 73.6% to 82.8% between surveyed interstitial lung disease (ILD) centres based entirely on the equation used. CONCLUSION: Substantial variability exists between reference equations, impacting access to subsidized treatment. Treating clinicians should be aware of this when assessing patients around public funding thresholds.

The efficacy and safety of mannitol challenge in a workplace setting for assessing asthma prevalence.

OBJECTIVE: There is no standard definition of asthma for epidemiological purposes; most surveys use symptoms and bronchial hyperresponsiveness. Few studies tested mannitol challenge test (MCT) in occupational settings. We sought to determine efficacy and safety of MCT in detecting subjects with asthma symptoms in the workplace. METHODS: In this cross-sectional study we recruited 908 workers in 2 universities; they underwent a respiratory questionnaire, spirometry, skin prick tests, and MCT. RESULTS: Eight hundred and eleven subjects completed the study; 11.1% had a positive MCT; 8.14% had asthma. MCT had low sensitivity (35.4-61.9%) but high specificity (90.2-94.9%) to detect symptomatic individuals. The most prevalent symptom was wheezing in the last 12 months. Twenty-four of those with a positive MCT (26.7%) had no positive replies to the questions on asthma symptoms. Among subjects with a positive MCT, 71.9% achieved 95% of baseline FEV1 after 15 minutes of salbutamol recovery treatment. Nine subjects (1.1%) had adverse events that prevented the test from being completed. CONCLUSIONS: MCT has high specificity but low sensitivity to detect symptomatic subjects in the workplace. It may detect subjects with hyperresponsiveness but no symptoms, who could be at risk of developing airway diseases. The test is safe and well tolerated.

Improving childcare staff management of acute asthma exacerbation - An Australian pilot study.

OBJECTIVE: This study aimed to evaluate the effectiveness of an asthma first-aid training tool for childcare staff in Australia. The effects of training on both asthma knowledge and skills were assessed. METHODS: A pre/post-study design was utilised to assess changes in asthma knowledge and asthma first-aid skills in childcare staff before and after an educational intervention. Asthma first-aid skills were assessed from the participant's response to two scenarios in which a child was having a severe exacerbation of asthma. Asthma knowledge and asthma skills scores were collected at base-line and 3 weeks post the education session, which involved feedback on each individual's skills and a brief lecture on asthma delivered via PowerPoint presentation. RESULTS: There was a significant improvement after intervention in asthma knowledge (Z = -3.638, p < 0.001) and asthma first-aid skills for both scenario 1 (Z = -6.012, p < 0.001) and scenario 2 (Z = -6.018, p < 0.001). In scenario 1 and 2, first-aid skills improved by 65% (p < 0.001) and 57% (p < 0.001), respectively. Asthma knowledge was high at baseline (79%) and increased by 7% (p < 0.001) after the educational intervention. These asthma knowledge results were not significant when adjusted for prior knowledge. Results suggest that knowledge assessment alone may not predict the practical skills needed for asthma first-aid. CONCLUSIONS: Skills assessment is a useful adjunct to knowledge assessment when gauging the ability of childcare staff to manage acute asthma exacerbation. Skills assessment could be considered for incorporation into future educational interventions to improve management of acute asthma exacerbation.

Exercise-induced bronchoconstriction update-2016.

The first practice parameter on exercise-induced bronchoconstriction (EIB) was published in 2010. This updated practice parameter was prepared 5 years later. In the ensuing years, there has been increased understanding of the pathogenesis of EIB and improved diagnosis of this disorder by using objective testing. At the time of this publication, observations included the following: dry powder mannitol for inhalation as a bronchial provocation test is FDA approved however not currently available in the United States; if baseline pulmonary function test results are normal to near normal (before and after bronchodilator) in a person with suspected EIB, then further testing should be performed by using standardized exercise challenge or eucapnic voluntary hyperpnea (EVH); and the efficacy of nonpharmaceutical interventions (omega-3 fatty acids) has been challenged. The workgroup preparing this practice parameter updated contemporary practice guidelines based on a current systematic literature review. The group obtained supplementary literature and consensus expert opinions when the published literature was insufficient. A search of the medical literature on PubMed was conducted, and search terms included pathogenesis, diagnosis, differential diagnosis, and therapy (both pharmaceutical and nonpharmaceutical) of exercise-induced bronchoconstriction or exercise-induced asthma (which is no longer a preferred term); asthma; and exercise and asthma. References assessed as relevant to the topic were evaluated to search for additional relevant references. Published clinical studies were appraised by category of evidence and used to document the strength of the recommendation. The parameter was then evaluated by Joint Task Force reviewers and then by reviewers assigned by the parent organizations, as well as the general membership. Based on this process, the parameter can be characterized as an evidence- and consensus-based document.

Mechanism of spirometry associated gastro-esophageal reflux in individuals undergoing esophageal assessment.

Persistent variability observed during spirometry, even when technical and personal factors are controlled, has prompted interest in uncovering its underlying mechanisms. Notably, our prior investigations have unveiled that spirometry has the potential to trigger gastro-esophageal reflux in a susceptible population. This current study embarks on elucidating the intricate mechanisms orchestrating reflux induced by spirometry. To achieve this, we enlisted twenty-four (24) participants exhibiting reflux symptoms for esophageal assessment. These participants underwent two sets of spirometry sessions, interspersed with a 10-minute intermission, during which we closely scrutinized fluid flow dynamics and esophageal function through high-resolution impedance esophageal manometry. Our comprehensive evaluation juxtaposed baseline manometric parameters against their equivalents during the initial spirometry session, the intervening rest period, and the subsequent spirometry session. Remarkably, impedance values, serving as a metric for fluid quantity, exhibited a substantial elevation during each spirometry session and the ensuing recovery interval in the pan-esophageal and hypopharyngeal regions when compared to baseline levels. Additionally, the resting pressure of the lower esophageal sphincter experienced a noteworthy reduction subsequent to the first bout of spirometry (13.6 ± 8.8 mmHg) in comparison to the baseline pressure (22.5 ± 13.3 mmHg). Furthermore, our observations unveiled a decline in spirometric parameters-FEV1 (0.14 ± 0.24 L, P = 0.042) and PEFR (0.67 L/s, P = 0.34)-during the second spirometry session when contrasted with the first session. Collectively, our study underscores the compelling evidence that spirometry maneuvers can elicit gastro-esophageal reflux by eliciting intra-esophageal pressure differentials and inducing temporary relaxation of the lower esophageal sphincter.

Feasibility and acceptability of using bronchial hyperresponsiveness to manage asthma in primary care: a pilot study.

AIMS: To determine if indirect testing for bronchial hyperresponsiveness (BHR) to monitor inhaled corticosteroid (ICS) treatment in asthma is feasible and acceptable in primary care. METHODS: Fourteen adult patients with asthma aged 22-70 years (4M:10F, forced expiratory volume in 1 s >70% predicted) taking ICS performed a test for BHR using mannitol on three visits 6 weeks apart. ICS dose adjustments were made based on the presence of BHR. The Asthma Quality of Life Questionnaire (AQLQ) and the Asthma Control Questionnaire were used at each visit. A semi structured interview at study exit assessed subject acceptability. RESULTS: BHR did not return in those with no BHR at study entry (n=9) with decreasing ICS dose. Improvements in BHR with increasing ICS dose (n=5) were observed with clinically significant improvements in AQLQ (mean score increase >0.5, p=0.02). Feasibility and acceptability of BHR testing was demonstrated. CONCLUSIONS: It is feasible and acceptable to perform BHR testing using mannitol to help identify patients with asthma who would benefit from ICS dose increases and those with no BHR who could have a dose reduction. TRIAL REGISTRATION: Australia New Zealand Clinical Trial Registry ACTRN12610000807055.

Daily Inhaled Corticosteroids Treatment Abolishes Airway Hyperresponsiveness to Mannitol in Defence and Police Recruits.

Background: Airway hyperresponsiveness (AHR) is a key pathophysiological feature of asthma and causes exercise-induced bronchoconstriction (EIB). Indirect bronchial provocation tests (BPTs) (e.g., exercise, mannitol) aid to diagnose asthma and identify EIB. Daily inhaled corticosteroids (ICS) can abolish AHR caused by indirect stimuli. Where strenuous physical exertion is integral to an occupation, identification of those at risk of EIB is important and documentation of inhibition of AHR with ICS is required before recruitment. Methods/Objectives: A retrospective analysis was performed on 155 potential recruits with AHR to mannitol who underwent follow-up assessment after daily ICS treatment to determine the proportion that can abolish AHR using ICS and to determine any predictors of the persistence of AHR. Results: Airway hyperresponsiveness was abolished in the majority (84%, n = 130) over the treatment period (mean ± SD 143 ± 72days), and it was defined as the provoking dose of mannitol to cause a 15% fall in FEV1 (cumulative inhaled dose of mannitol to cause 15% fall in FEV1, PD15) improved from (GeoMean) 183 to 521 mg. Compared with recruits in whom AHR was abolished with daily ICS (i.e., no 15% fall in FEV1 to the maximum cumulative dose of mannitol of 635 mg), in those where AHR remained (16%, n = 25), baseline AHR was more severe (PD15: 85 mg vs. 213 mg, P < 0.001), baseline FEV1% was lower (89 vs. 96%; 95%CI:2-12, P=0.004), and they had a longer follow-up duration (180 vs. 136 days; 13-74, P = 0.006). Baseline FEV1% (adjusted odds ratio 0.85; 95%CI:0.77-0.93), FEV1/FVC (0.78; 0.67-0.90), FEF25-75% (1.15; 1.06-1.25), and airway reactivity to mannitol (%Fall/cumulative dose of mannitol multiplied by 100) (1.07; 1.03-1.11) predicted AHR remaining after daily ICS. Conclusion: Airway hyperresponsiveness to mannitol can be abolished after 20 weeks of daily treatment with ICS. Inhibition of AHR is likely due to attenuation of airway inflammation in response to ICS treatment. Increased airway reactivity and lower spirometry variables predicted the persistence of AHR. Thus, those with a slower response to daily ICS on AHR can potentially be identified at the commencement of monitoring ICS using inhaled mannitol.

The Need for Testing-The Exercise Challenge Test to Disentangle Causes of Childhood Exertional Dyspnea.

Exertional dyspnea is a common symptom in childhood which can induce avoidance of physical activity, aggravating the original symptom. Common causes of exertional dyspnea are exercise induced bronchoconstriction (EIB), dysfunctional breathing, physical deconditioning and the sensation of dyspnea when reaching the physiological limit. These causes frequently coexist, trigger one another and have overlapping symptoms, which can impede diagnoses and treatment. In the majority of children with exertional dyspnea, EIB is not the cause of symptoms, and in asthmatic children it is often not the only cause. An exercise challenge test (ECT) is a highly specific tool to diagnose EIB and asthma in children. Sensitivity can be increased by simulating real-life environmental circumstances where symptoms occur, such as environmental factors and exercise modality. An ECT reflects daily life symptoms and impairment, and can in an enjoyable way disentangle common causes of exertional dyspnea.

Sodium cromoglycate alone and in combination with montelukast on the airway response to mannitol in asthmatic subjects.

BACKGROUND: Mannitol, inhaled as a dry powder, is used for bronchial provocation to identify bronchial hyperresponsiveness. Bronchoconstriction is associated with an increase in urinary excretion of the metabolites of prostaglandin D(2) and leukotriene E(4). Sodium cromoglycate provides about 60% protection against the fall in forced expiratory volume in one second (FEV(1)) provoked by inhaled mannitol and appears to do so by inhibiting the release of prostaglandin D(2) but not leukotriene E(4).The leukotriene receptor antagonist montelukast does not alter sensitivity to mannitol, as measured by the provoking dose to cause a 15% fall in FEV(1) to mannitol, but it significantly enhances recovery from the bronchoconstriction provoked by mannitol. OBJECTIVE: The authors proposed that the combination of these two drugs would be superior to sodium cromoglycate alone and result in greater protection from the bronchoconstriction provoked by mannitol. METHODS: The % fall in FEV(1) from baseline and the area under the 30-min FEV(1) time curve and time to recover to 95% baseline FEV(1) were used to express protection from 40 mg sodium cromoglycate alone, and in combination with 10 mg montelukast, in subjects with asthma. Mannitol was inhaled in the dose that caused a 20% fall in FEV(1) on the screening day. The prechallenge medications were randomised on the 3 treatment days and were (1) placebo sodium cromoglycate and placebo montelukast; (2) sodium cromoglycate and placebo montelukast; and (3) sodium cromoglycate and montelukast. RESULTS: The protection by sodium cromoglycate alone on the % fall in FEV(1) was 64.4% +/- 21.0% versus 65.8% +/- 62.8% (p = NS) on the combination. The protection on the area under the 30-min FEV(1) time curve for sodium cromoglycate was 81.8% +/- 14.0% (p <.04) and 89.3% +/- 9.8% for the combination (p <.001) compared with placebo. Recovery to 95% baseline FEV(1) by 5/10 min occurred in 58%/66% of subjects on sodium cromoglycate and 66%/83% on the combination compared with 0%/0% on placebo. CONCLUSION: The addition of montelukast to sodium cromoglycate provided only a small additional benefit against the airway response to mannitol.

Airway hyperresponsiveness to methacholine, adenosine 5-monophosphate, mannitol, eucapnic voluntary hyperpnoea and field exercise challenge in elite cross-country skiers.

BACKGROUND: Methacholine hyperresponsiveness is prevalent in elite athletes. Comparative studies have hitherto been limited to methacholine, eucapnic voluntary hyperpnoea and exercise. This study investigated airway responsiveness to these stimuli as well as to adenosine 5'-monophosphate (AMP) and mannitol, in 58 cross-country ski athletes. METHODS: Exhaled nitric oxide concentration (F(E)NO), spirometry and bronchial challenge in random order with methacholine, AMP and mannitol were consecutively performed on three study days in the autumn. Specific IgE to eight aeroallergens and a self-completed questionnaire about respiratory symptoms, allergy and asthmatic medication were also performed on day 1. Eucapnic voluntary hyperventilation (EVH) and field exercise tests were randomly performed in 33 of the skiers on two study days in the following winter. RESULTS: Of 25 (43%) skiers with airway hyperresponsiveness (AHR), 23, five and three skiers were hyperresponsive to methacholine, AMP and mannitol, respectively. Methacholine hyperresponsiveness was more prevalent in subjects without asthma-like symptoms. The F(E)NO was not significantly different in skiers with and without methacholine hyperresponsiveness. Four of 14 skiers with and four of 19 skiers without methacholine hyperresponsiveness were hyperresponsive to EVH or exercise challenge. AHR to any stimulus was present in 16 asymptomatic and nine symptomatic skiers. Asthma-like symptoms were not correlated with AHR to any stimulus. CONCLUSIONS: Methacholine hyperresponsiveness is more common in asymptomatic skiers and is a poor predictor of hyperresponsiveness to mannitol and hyperpnoea. The low prevalence of hyperresponsiveness to indirect stimuli may suggest differences in the pathogenesis of methacholine hyperresponsiveness in elite skiers and non-athletes.

Prolonged bronchoprotection against inhaled methacholine by inhaled BI 1744, a long-acting beta(2)-agonist, in patients with mild asthma.

BACKGROUND: Long-acting ss(2)-agonists are an established controller medication in asthma. BI 1744 is a novel L\long-acting ss(2)-agonist with a preclinical profile that suggests 24-hour bronchodilation and bronchoprotection may be achieved. OBJECTIVE: To examine the bronchoprotective effects of single doses of BI 1744 against methacholine provocation in subjects with mild asthma. METHODS: Thirty-one subjects with mild asthma were randomized to receive single doses of BI 1744 (2, 5, 10, 20 microg) or placebo on separate days according to a double-blind, 5-way crossover design. Methacholine challenges were performed at 30 minutes and at 4, 8, 24, and 32 hours after each single dose of medication, and the results were expressed as PC(20) FEV(1). RESULTS: All doses of BI 1744 produced statistically significant increases in the methacholine PC(20) compared with placebo as long as 32 hours. The mean (geometric SEM) methacholine PC(20) 24 hours after dosing with placebo was 1.73 (1.13) mg/mL, which increased after 2 microg to 3.86 (1.14) mg/mL, after 5 microg to 5.67 (1.14) mg/mL, after 10 microg to 9.42 (1.13) mg/mL, and after 20 microg to 13.71 (1.14) mg/mL (all P < .0001). After 32 hours, the methacholine PC(20) value remained significantly increased for all doses. No safety or tolerability concerns were identified. CONCLUSION: BI 1744 provides significant bronchoprotection against inhaled methacholine for up to 32 hours after single-dose administration.

The inflammatory basis of exercise-induced bronchoconstriction.

Exercise-induced bronchoconstriction (EIB) is common in individuals with asthma, and may be observed even in the absence of a clinical diagnosis of asthma. Exercise-induced bronchoconstriction can be diagnosed via standardized exercise protocols, and anti-inflammatory therapy with inhaled corticosteroids (ICS) is often warranted. Exercise-related symptoms are commonly reported in primary care; however, access to standardized exercise protocols to assess EIB are often restricted because of the need for specialized equipment, as well as time constraints. Symptoms and lung function remain the most accessible indicators of EIB, yet these are poor predictors of its presence and severity. Evidence suggests that exercise causes the airways to narrow as a result of the osmotic and thermal consequences of respiratory water loss. The increase in airway osmolarity leads to the release of bronchoconstricting mediators (eg, histamine, prostaglandins, leukotrienes) from inflammatory cells (eg, mast cells and eosinophils). The objective assessment of EIB suggests the presence of airway inflammation, which is sensitive to ICS in association with a responsive airway smooth muscle. Surrogate tests for EIB, such as eucapnic voluntary hyperpnea or the osmotic challenge tests, cause airway narrowing via a similar mechanism, and a response indicates likely benefit from ICS therapy. The complete inhibition of EIB with ICS therapy in individuals with asthma may be a useful marker of control of airway pathology. Furthermore, inhibition of EIB provides additional, useful information regarding the identification of clinical control based on symptoms and lung function. This article explores the inflammatory basis of EIB in asthma as well as the effect of ICS on the pathophysiology of EIB.

Bronchial Provocation Testing for the Identification of Exercise-Induced Bronchoconstriction.

Exercise-induced bronchoconstriction (EIB) occurs in patients with asthma, children, and otherwise healthy athletes. Poor diagnostic accuracy of respiratory symptoms during exercise requires objective assessment of EIB. The standardized tests currently available are based on the assumption that the provoking stimulus to EIB is dehydration of the airway surface fluid due to conditioning large volumes of inhaled air. "Indirect" bronchial provocation tests that use stimuli to cause endogenous release of bronchoconstricting mediators from airway inflammatory cells include dry air hyperpnea (eg, exercise and eucapnic voluntary hyperpnea) and osmotic aerosols (eg, inhaled mannitol). The airway response to different indirect tests is generally similar in patients with asthma and healthy athletes with EIB. Furthermore, the airway sensitivity to these tests is modified by the same pharmacotherapy used to treat asthma. In contrast, pharmacological agents such as methacholine, given by inhalation, act directly on smooth muscle to cause contraction. These "direct" tests have been used traditionally to identify airway hyperresponsiveness in clinical asthma but are less useful to diagnose EIB. The mechanistic differences between indirect and direct tests have helped to elucidate the events leading to airway narrowing in patients with asthma and elite athletes, while improving the clinical utility of these tests to diagnose and manage EIB.

Prevalence and effects of gastro-oesophageal reflux during spirometry in subjects undergoing reflux assessment.

Variability during spirometry can persist despite control of technical and personal factors. We postulate spirometry induces gastro-oesophageal reflux (GOR), which may cause variability and affect results of spirometry. Fifty-eight (58) subjects undergoing GOR investigation with oesophageal manometry and 24hr pH monitoring were recruited. Oesophageal dysmotility and GOR were assessed as part of clinical care. Subjects performed 2 sets of spirometry separated by a 10-minute rest period. The assessment of GOR during spirometry procedure (defined by a lower oesophageal pH<4) started from the first set of spirometry and concluded when the second set of spirometry was completed. We calculated variability (%) of FEV1, FVC and PEFR within each set as well as changes over 10-minutes. Twenty-six subjects (45%) recorded GOR during assessment. Of these, 23 subjects recorded GOR during the 10-minute rest period. Four subjects had GOR recorded only during spirometry tests. We did not find variability of spirometry parameters between the groups with and without GOR during spirometry procedure. However, in subjects with GOR, we found small but significant reductions of PEFR (0.5L/s, 8%, p<0.001) and FEV1 (84 mL, 3%, p = 0.048) in the second set of spirometry compared to the first spirometry set. This pilot study demonstrates that GOR can occur during and following spirometry. Presence of GOR during spirometry in this patient population caused small decreases in PEFR and FEV1 when it is repeated 10-minutes later however not increase variability in a single series of measurements.

Cough as an adverse effect on inhalation pharmaceutical products.

Cough is an adverse effect that may hinder the delivery of drugs into the lungs. Chemical or mechanical stimulants activate the transient receptor potential in some airway afferent nerves (C-fibres or A-fibres) to trigger cough. Types of inhaler device and drug, dose, excipients and formulation characteristics, including pH, tonicity, aerosol output and particle size may trigger cough by stimulating the cough receptors. Release of inflammatory mediators may increase the sensitivity of the cough receptors to stimulants. The cough-provoking effect of aerosols is enhanced by bronchoconstriction in diseased airways and reduces drug deposition in the target pulmonary regions. In this article, we review the factors by which inhalation products may cause cough.

Comparison of mannitol and citric acid cough provocation tests.

RATIONALE: Citric acid has been used as a cough provocation test for decades. However, the methods of administration have not been standardized. Inhaled mannitol is a novel cough provocation test, which has regulatory approval and can be performed utilizing a simple disposable inhaler in a standardized manner. OBJECTIVE: To compare the mannitol and citric acid cough provocation tests with respect to their ability to identify subjects with chronic cough and their tolerability. METHODS: Subjects with chronic cough (n = 36) and controls (n = 25) performed provocation tests with mannitol and citric acid. Both tests were video recorded. Cough sensitivity was expressed as coughs-to-dose ratios (CDR) and the cumulative doses to mannitol or concentration to citric acid evoking 5 coughs (C5). Forced expiratory volume in 1 s (FEV1), visual analogue scales (VAS), test completion rates and the total cough frequencies were analysed. RESULTS: Mannitol and citric acid CDR both effectively separated those with cough and the control subjects (AUC 0.847 and 0.803, respectively) as did C5 (AUC 0.823 and 0.763, respectively). There was a good correlation between the cough sensitivity provoked by the two stimuli, either expressed as CDR (r = 0.65, p < 0.001) or C5 (r = 0.53, p = 0.001). Both tests were similarly tolerated in terms of VAS, although more patients discontinued the mannitol test early, primarily due to cough. CONCLUSIONS: Mannitol and citric acid tests correlated well, equally identified subjects with chronic cough and their tolerability was similar. The feasibility issues, strict standardisation and regulatory approval may favour mannitol to be used in clinical cough research.